The initiation of a hand grip is delayed by silently reading an incompatible syllable.

The movements of phonation structures (e.g., tongue) have been shown to facilitate compatible hand movements. For example, reaction time (RT) of precision and power hand grips (made with tips of thumb and finger vs. whole hand) are shortened with the production of syllables that share similar action features (e.g., employing the proximal vs. dorsal portion of the tongue, respectively). This effect is coined the articulation-grip correspondence (AGC) effect. However, it is not known if the AGC effect is due to action facilitation vs. interference, and if such facilitation/ interference is due to covertly or overtly reading the syllable. To answer the associated empirical questions, the present experiment involved participants initiating a precision or power grip without the covert/ overt reading of a syllable, or while covertly or overtly reading the syllable /ti/ or /ka/. In both the covert and overt reading conditions, there were longer RTs for precision grips with the syllable /ka/ than /ti/, and there were longer RTs for power grips with the syllable /ti/. In contrast, the syllable /ti/ or /ka/ did not alter precision or power grip RTs, respectively. These findings support the notion of articulation-grip interference but not facilitation and that such interference can be observed with covert (silent) reading.

Orofacial clefts embryology, classification, epidemiology, and genetics.

Orofacial clefts (OFCs) rank as the second most common congenital birth defect in the United States after Down syndrome and are the most common head and neck congenital malformations. They are classified as cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO). OFCs have significant psychological and socio-economic impact on patients and their families and require a multidisciplinary approach for management and counseling. A complex interaction between genetic and environmental factors contributes to the incidence and clinical presentation of OFCs. In this comprehensive review, the embryology, classification, epidemiology and etiology of clefts are thoroughly discussed and a "state-of-the-art" snapshot of the recent advances in the genetics of OFCs is presented.

Dysregulation of Rho GTPases in orofacial cleft patients-derived primary cells leads to impaired cell migration, a potential cause of cleft/lip palate development.

Cleft lip and/or palate are a split in the lip, the palate or both. This results from the inability of lip buds and palatal shelves to properly migrate and assemble during embryogenesis. By extracting primary cells from a cleft patient, we aimed at offering a better understanding of the signaling mechanisms and interacting molecules involved in the lip and palate formation and fusion. With Rho GTPases being indirectly associated with cleft occurrence, we investigated the role of the latter in both. First, whole exome sequencing was conducted in a patient with cleft lip and palate. Primary fibroblastic cells originating from the upper right gingiva region were extracted and distinct cellular populations from two individuals were obtained: a control with no cleft phenotype and a patient with a cleft lip and palate. The genetic data showed three candidate variables in ARHGEF18, EPDR1, and CUL7. Next, the molecular data showed no significant change in proliferation rates between healthy patient cells and CL/P patient cells. However, CL/P patient cells showed decreased migration, increased adhesion and presented with a more elongated phenotype. Additionally, RhoA activity was upregulated in these cells, whereas Cdc42 activity was downregulated, resulting in loss of polarity. Our results are suggestive of a possible correlation between a dysregulation of Rho GTPases and the observed phenotype of cleft lip and palate patient cells. This insight into the intramolecular aspect of this disorder helps link the genetic defect with the observed phenotype and offers a possible mechanism by which CL/P occurs.

Altered regulation of cell migration in IRF6-mutated orofacial cleft patients-derived primary cells reveals a novel role of Rho GTPases in cleft/lip palate development.

Orofacial clefts are the most common congenital craniofacial birth defects. They occur from a failure in cell proliferation and fusion of neural crest cells of the lip buds and/or palatal shelves. In this study, we investigate the genetic basis and molecular mechanisms in primary cells derived from a cleft and lip palate patient presenting van der Woude syndrome (VWS). Since mutations in the integrin genes are widely correlated with VWS, Interferon Regulatory Factor 6 (IRF6) screening was conducted in a cohort of 200 participants presenting with orofacial anomalies. Primary fibroblastic cells derived from the upper right gingiva and palatal regions were isolated and two cellular populations from two participants were obtained: a control with no cleft phenotype and a patient with a cleft phenotype typical of van der Woude syndrome (VWS). IRF6 targeted sequencing revealed mutations in two distinct families. Our results showed no alteration in the viability of the CLP/VWS patient cells, suggesting the phenotype associate with the disease is not secondary to a defect in cell proliferation. We did however detect a significant decrease in the migratory ability of the CLP with Van der Woude syndrome (CLP/VWS) patient cells, which could account for the phenotype. When compared to normal cells, patient cells showed a lack of polarization, which would account for their lack of mobility. Patient cells showed protrusions all around the cells and a lack of defined leading edge. This was reflected with actin staining, WAVE2 and Arp2 around the cell, and correlated with an increase in Rac1 activation. Consistently with the increase in Rac1 activation, patient cells showed a loss in the maturation of focal adhesions needed for contractility, which also accounts for the lack in cell migration. Our findings give increased understanding of the molecular mechanisms of VWS and expands the knowledge of van der Woude syndrome (VWS) occurrence by providing a strong molecular evidence that CLP with Van der Woude syndrome (CLP/VWS) phenotype is caused by a defect in normal physiological processes of cells.

The long non coding RNA H19 as a biomarker for breast cancer diagnosis in Lebanese women.

Breast cancer is the most common cancer in women worldwide. Minimally invasive percutaneous image-guided biopsies are the current cornerstone in the diagnosis of breast lesions detected on mammography/ultrasonography/MRI or palpable clinically. However, apparently benign breast disease seen on benign biopsies is a limiting factor for diagnosis and a risk factor of breast cancer especially in the high-risk category patients. Hypothesizing that molecular changes often occur before morphological variations, the levels of the LncRNA H19 were measured in anonymous tissues obtained from 79 women's image guided breast biopsies, and correlated with cancer progression and aggressiveness. Using a double-blinded approach, H19 might be attributed an interesting role of a more sensitive biomarker in core breast biopsies, independently of the radiological/clinical classification and distant from the clinical management. We established different thresholds for H19 levels in normal versus proliferative, versus malignant tissues. Additionnally, H19 could act as an intra-group risk marker categorizing the biopsies in normal versus benign, versus precancerous breast tissue, and as a prognostic factor in cancerous lesions discriminating aggressive versus nonaggressive lesions. Our study suggests that the lncRNA H19 could be a potential marker for breast cancer diagnosis, prognosis and risk management.

High-intensity transcranial magnetic stimulation reveals differential cortical contributions to prepared responses.

Corticospinal output pathways have typically been considered to be the primary driver for voluntary movements of the hand/forearm; however, more recently, reticulospinal drive has also been implicated in the production of these movements. Although both pathways may play a role, the reticulospinal tract is thought to have stronger connections to flexor muscles than to extensors. Similarly, movements involuntarily triggered via a startling acoustic stimulus (SAS) are believed to receive greater reticular input than voluntary movements. To investigate a differential role of reticulospinal drive depending on movement type or acoustic stimulus, corticospinal drive was transiently interrupted using high-intensity transcranial magnetic stimulation (TMS) applied during the reaction time (RT) interval. This TMS-induced suppression of cortical drive leads to RT delays that can be used to assess cortical contributions to movement. Participants completed targeted flexion and extension movements of the wrist in a simple RT paradigm in response to a control auditory go signal or SAS. Occasionally, suprathreshold TMS was applied over the motor cortical representation for the prime mover. Results revealed that TMS significantly increased RT in all conditions. There was a significantly longer TMS-induced RT delay seen in extension movements than in flexion movements and a greater RT delay in movements initiated in response to control stimuli compared with SAS. These results suggest that the contribution of reticulospinal drive is larger for wrist flexion than for extension. Similarly, movements triggered involuntarily by an SAS appear to involve greater reticulospinal drive, and relatively less corticospinal drive, than those that are voluntarily initiated. NEW & NOTEWORTHY Through the use of the transcranial magnetic stimulation-induced silent period, we provide novel evidence for a greater contribution of reticulospinal drive, and a relative decrease in corticospinal drive, to movements involuntarily triggered by a startle compared with voluntary movements. These results also provide support for the notion that both cortical and reticular structures are involved in the neural pathway underlying startle-triggered movements. Furthermore, our results indicate greater reticulospinal contribution to wrist flexion than extension movements.

Visual processing is diminished during movement execution.

Recent research has suggested that visual discrimination and detection may be enhanced during movement preparation and execution, respectively. The current study examined if visual perceptual processing is augmented prior to or during a movement through the use of an Inspection Time (IT) task. The IT task involved briefly presenting (e.g., 15-105 ms) a "pi" figure with differing leg lengths, which was then immediately masked for 400 ms to prevent retinal afterimages. Participants were subsequently required to choose which of the two legs was longer. In Experiment 1, participants (n = 28) completed the IT task under three movement conditions: no-movement (NM), foreperiod (FP), and peak velocity (PV). In the NM condition, participants solely engaged in the IT paradigm. In the FP condition, the IT stimulus was presented prior to movement execution when response planning was expected to occur. Finally, in the PV condition, participants made a rapid movement to a target, and the IT stimulus was presented when their limb reached peak velocity. In Experiment 2, participants (n = 18) also performed the IT task in the PV and NM condition; however, vision of the limb's motion was made available during the PV trials (PV-FV) to investigate the potential influence of visual feedback on IT performance. Results showed no significant differences in performance in the IT task between the NM and FP conditions, suggesting no enhancement of visual processing occurred due to response preparation (Experiment 1). However, IT performance was significantly poorer in the PV condition in comparison to both the NM and FP conditions (Experiment 1), and was even worse when visual feedback was provided (Experiment 2). Together, these findings suggest that visual perceptual processing is degraded during execution of a fast, goal-directed movement.

Telomerase regulation by the long non-coding RNA H19 in human acute promyelocytic leukemia cells.

BACKGROUND: Since tumor growth requires reactivation of telomerase (hTERT), this enzyme is a challenging target for drug development. Therefore, it is of great interest to identify telomerase expression and activity regulators. Retinoids are well-known inducers of granulocytic maturation associated with hTERT repression in acute promyelocytic leukemia (APL) blasts. In a maturation-resistant APL cell line, we have previously identified a new pathway of retinoid-induced hTERT transcriptional repression independent of differentiation. Furthermore, we reported the isolation of a cell variant resistant to this repression. Those cell lines could serve as unique tools to identify new telomerase regulators. METHODS: Using a microarray approach we identified the long non-coding RNA, H19 as a potential candidate playing a role in telomerase regulation. Expression of H19, hTERT, and hTR were examined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Telomerase activity was quantified by quantitative telomeric repeats amplification protocol (qTRAP). In vitro and in vivo assays were performed to investigate H19 function on telomerase expression and activity. RESULTS: We showed both in retinoid-treated cell lines and in APL patient cells an inverse relationship between the expression of H19 and the expression and activity of hTERT. Exploring the mechanistic link between H19 and hTERT regulation, we showed that H19 is able to impede telomerase function by disruption of the hTERT-hTR interaction. CONCLUSIONS: This study identifies a new way of telomerase regulation through H19's involvement and thereby reveals a new function for this long non-coding RNA that can be targeted for therapeutic purpose.

Coactivation of response initiation processes with redundant signals.

During reaction time (RT) tasks, participants respond faster to multiple stimuli from different modalities as compared to a single stimulus, a phenomenon known as the redundant signal effect (RSE). Explanations for this effect typically include coactivation arising from the multiple stimuli, which results in enhanced processing of one or more response production stages. The current study compared empirical RT data with the predictions of a model in which initiation-related activation arising from each stimulus is additive. Participants performed a simple wrist extension RT task following either a visual go-signal, an auditory go-signal, or both stimuli with the auditory stimulus delayed between 0 and 125 ms relative to the visual stimulus. Results showed statistical equivalence between the predictions of an additive initiation model and the observed RT data, providing novel evidence that the RSE can be explained via a coactivation of initiation-related processes. It is speculated that activation summation occurs at the thalamus, leading to the observed facilitation of response initiation.

Gastrointestinal cancer cells treatment with bevacizumab activates a VEGF autoregulatory mechanism involving telomerase catalytic subunit hTERT via PI3K-AKT, HIF-1α and VEGF receptors.

BACKGROUND: Targeting angiogenesis has been considered a promising treatment of choice for a large number of malignancies, including gastrointestinal cancers. Bevacizumab is an anti-vascular endothelial growth factor (anti-VEGF) being used for this purpose. However, treatment efficacy is largely questioned. Telomerase activity, responsible for cancer cell immortality, is detected in 85-95% of human cancers and is considered a potential regulator of VEGF. The aim of our study was to investigate the interrelationship between VEGF and hTERT in gastrointestinal cancers and to explore cell response to a combined inhibition of telomerase and VEGF. METHODS: AGS (gastric cancer), Caco-2 (colorectal cancer) and HepG2/C3A (hepatocellular carcinoma), were treated with telomerase inhibitors BIBR-1232 (10µM) and costunolide (10µM), with bevacizumab (Avastin® at 5 ng/ml or 100µg/ml) or with a combination of both types of inhibitors. VEGF and hTERT mRNA levels, and telomerase activity were detected by RT-PCR. VEGF levels were quantified by ELISA. Telomerase was knocked down using hTERT siRNA and hTERT was overexpressed in the telomerase negative cell line, Saos-2 (osteosarcoma), using constructs expressing either wild type hTERT (hTERT-WT) or dominant negative hTERT (hTERT-DN). Tube formation by HUVECs was assessed using ECMatrix™ (EMD Millipore). RESULTS: Our results showed that telomerase regulates VEGF expression and secretion through its catalytic subunit hTERT in AGS, Caco2, and HepG2/C3A, independent of its catalytic activity. Interestingly, VEGF inhibition with bevacizumab (100µg/ml) increased hTERT expression 42.3% in AGS, 94.1% in Caco2, and 52.5% in HepG2/C3A, and increased telomerase activity 30-fold in AGS, 10.3-fold in Caco2 and 8-fold in HepG2/C3A. A further investigation showed that VEGF upregulates hTERT expression in a mechanism that implicates the PI3K/AKT/mTOR pathway and HIF-1α. Moreover, bevacizumab treatment increased VEGFR1 and VEGFR2 expression in cancer cells and human umbilical vein endothelial cells (HUVECs) through hTERT. Thus, the combination of bevacizumab with telomerase inhibitors decreased VEGF expression and secretion by cancer cells, inhibited VEGFR1 and VEGFR2 upregulation, and reduced tube formation by HUVECs. CONCLUSIONS: Taken together, our results suggest that bevacizumab treatment activates a VEGF autoregulatory mechanism involving hTERT and VEGF receptors and that an inhibition of this pathway could improve tumor cell response to anti-VEGF treatment.